Definition of paraneoplastic syndromes in Robbin's Basic Pathology:

The most common biologically active substance secreted from carcinoid tumors is 5-HT (serotonin), a vasoactive peptide whose biosynthesis is accomplished nearly exclusively by the enterochromaffin cells. Synthesized from the amino acid tryptophan, the release of 5-HT into the systemic circulation can cause the classic symptoms of the carcinoid syndrome, which include diarrhea, episodic flushing, bronchoconstriction, and eventual right-sided valvular heart disease

Cytokines play a major role in cancer cachexia.
In fact, replacement of nutrition may not reverse the cachexia. Source

Depression

#psychiatry
Monoamine theory of depression.
It has been theorized that depression results from a deficiency of monoamine neurotransmitters.
Monoamine neurotransmitters include serotonin (5-HT) and noradrenaline.

Antidepressant drugs

Monoamine uptake inhibitors

SSRI: Fluoxetine, sertraline, citalopram, escitalopram
TCA: clomipramine, imipramine, amitriptyline
Newer, mixed 5-HT and noradrenaline reuptake inhibitors (SNRI) : venlafaxine, duloxetine. (less selective for 5-HT than SSRIs)
Noradrenaline reuptake inhibitors : bupropion, atomoxetine
St. John's wort - weak monoamine uptake inhibitor.

Monoamine receptor antagonists

Mirtazapine

Monoamine oxidase inhibitors

Irreversible non competitive : phenelzine
Reversible MAO-A selective - moclobemide.

#2022BSQ-NOW Q32
Serotonin (aka 5-hydroxytryptamine(5-HT) is a monoamine neurotransmitter.

Pathophysiology

Serotonin has diverse effects. ]

1. CNS: modulates attention, behaviour and thermoregulation
2. Peripheral: produced by enterochromaffin cells -> regulates gastric motility, vasoconstriction, uterine contraction and bronchoconstriction.
3. Also promotes platelet aggregation

Stimulation of the postsynaptic 5-HT1A and 5-HT2A receptors has been implicated in serotonin syndrome.

Serotonin toxicity (increased serotonin activity in the CNS) in the brain.
Commonest with MAOIs.
SSRIs have less potential for SS but still cause it.
SNRIs have higher potential for SS than SSRIs.

Life threatening!.

The syndrome is classically associated with the simultaneous administration of two serotonergic agents, but it can occur after initiation of a single serotonergic drug or increasing the dose of a serotonergic drug in individuals who are particularly sensitive to serotonin.

It is a Clinical diagnosis. No laboratory testing available.
Classically described as a tried of

1. mental status changes,
2. autonomic hyperactivity
3. neuromuscular abnormalities

Highly suggestive features (based on the groups above): (based on Hunter criteria for diagnosis)

1. agitation, akathisia
2. Diaphoresis
3. Temperature > 38
4. Clonus
5. Hyperreflexia
6. Tremor

• occular clonus - Slow, continuous, horizontal eye movements
• Increased bowel sounds
  | Meningitis with accompanying meningococcaemia | 60% |
  [[2022 May Basic Sciences#Meningococcal vaccination]]

| Saturation kinetics at high dose | First order kinetics |

[[2022 May Basic Sciences#Cholera vaccine|Cholera vaccine]]
#TODO
Treatment of malaria in #pregnancy

Full house pattern only means activation of complement pathway: it's not specific for SLE.

Source

• Nephrotic syndrome (MMF)

  • FSGS

• Nephritic syndrome (= glomerulonephritis)

  • ? infective endocarditis associated nephropathy

• Mixed nephritic / nephrotic pictures

• Asymptomatic haematuria and / or proteinuria

Nephrotic range proteinuria

General problems caused by nephrotic range proteinuria

1. High protein diet is not advisable.
2. Hypercoaulable states can occur, specially with membranous nephropathy.
3. Sepsis is a major cause of death due to loss of immunoglobulin -> pneumococcal infections
4. Lipid abnormalities -> increased cardiovascular risk.
5. ACEi / ARB are indicated for all patients with nephrotic range proteinuria.

MCD / Membranous / FSGS => ''MMF''

Children: Commonest cause is minimal change disease
Adults: 30% have systemic disease :

Remainder

MCD

Only rarely leads to CKD.

Membranous

Membranous nephropathy -

• Diffuse glomerular membrane thickening with normal cellularity
• Subepithelial deposits, granular IgG deposition. Immunofluorescence patter: granular.
• The subepithelial deposits cause the basement membrane to thicken with visible 'spike' formation. Spikes eventually encase the deposited immune complexes.
• Membrane damage is likely compliment mediated.
• Majority of cases are caused by autoantibodies directed against the phospholipase A2 receptor (PLA2R) found on podocytes.
• Others are caused by secondary causes:
• Most often idiopathic. Need to exclude hepatitis B, SLE, thyroiditis, some drugs (penicillamine, gold / mercury, captopril)

Clinical

• Commonest in men
• Slowly progressive (onset 30 to 60 years)
• About 1/3 have spontaneous remission. 40% go on to have CKD; proteinuria is often persistent even if there's no CKD.
• Non selective protein loss;
• Poor response to steroids
• ALL PATIENTS SHOULD RECEIVE MAXIMUM DOSE OF ACE-I.
• Immunomodulatory therapy is useful.

Membranous nephropathy is the one most likely to occur secondary to a cancer. (i.e paraneoplastic) - PasTest

[!TIP] Haematuria with associated Proteinuria suggest glomerulonephritis rather than macroscopic bleed.
(I.e renal biopsy is more suitable than cystoscopy)

FSGS

FSGS recurs in transplanted kidneys.
| Primary FSGS | Secondary FSGS |
| -------------------------------------------------------------------------------------------------- | ------------------------------------------------------------------------------------------- |
| Sometimes responds to steroids, failure of steroids is common. Other immunosuppresants are used. | Usually poor response to steroids. ACEi are better |
| Presents as massive proteinuria, haematuria and hypertension. | Can be caused by any process which reduces functioning number of nephrons (eg. nephrectomy) |
| | (nephrectomy, hypertension, gross obesity, IgA nephropathy, HIV, CMV, EBV) |

Minimal change Vs. FSGS

[!TIP]
MCD and FSGS are like cousins; similar but different

Haematuria is commoner in FSGS than in MCD.
MCD shows selective protein loss -> i.e mainly albumin and not higher molecular weight proteins like immunoglobulins. FSGS shows non-selective proteinuria.
FSGS shows poor response to corticosteroids.
Higher percentage of FSGS patients go on to develop CKD (50%). (adults have worse prognosis)
MCD and FSGS both show minimal / no immune deposits.
FSGS : FSGS changes on light microscopy. MCD: few changes visible on light microscopy.

Causes of nephritic picture

IgA nephropathy

1. The commonest glomerular disease found on biopsy!
2. It causes recurring episodes of microscopic or gross haematuria lasting a few days. Usually reccurs every few months after the onset.
3. Affects children and young adults
4. Begins with haematuria 1-2 days after non specific upper respiratory tract infection.
5. Hallmark is IgA deposition in the mesangium.
6. May be related to Henoch Schonlein purpura which has mesangial IgA deposition as well as systemic involvement.
7. Pathogenesis may be due to abnormally increased IgA production.
8. IgA based immune complexes activate the alternate complement pathway -> Glomerular injury.
9. Histology: There is diffuse mesangioproliferation.
10. Progression to CKD is slow (if at all - occurs in about 40 of cases)
    
    
    D - mesangial deposits

Membranoproliferative glomerulonephritis

mixed nephrotic / nephritic picture. => nephrotic Xn + haematuria, hypertension and impaired renal function
Most patients will go on to develop ESKD over several years;
recurs in renal transplant patients.
C3 complement levels are low.
Type 1 <= activation classical complement pathway - low C3 levels, normal C4 levels. (Tramline pattern seen)
Type 2 <= activation of alternative complement pathway

Renal [[Tuberculosis]]

Neuro: if severe, tonic clonic seizure and coma.

General rules applicable to vaccination

1. Severely immunocompromised patients
2. Women known to be pregnant
3. Patients with encephalopathy follwing pretussis containing vaccine
4. SCID and intussusception are contraindications for rotavirus vaccine.
5. Two live vaccinations can be given on the same day but if they are not given on the same day, there must be a 4 week gap between then because the first vaccine can decrease the response to the second.

There is no hepatitis C vaccine.

The commonest contraindications for vaccination are

1. Previous severe allergic reaction
2. Immunosuppresion
   1. Live attenuated influenza - (also contraindicated in close contacts / caregivers of immunosuppressed patients!)
   2. MMR - contraindicated even with a family history of altered immunity.
   3. Varicella (chicken pox) vaccine
   4. Dengue vaccine
3. Pregnancy
   1. Live attenuated influenza vaccine
   2. MMR
   3. Varicella (chicken pox) vaccine

• Hepatitis B vaccine can definitely be given in pregnancy. Source
• The HPV vaccine is a protein sub-unit based vaccine. (no live viral particles)-> HPV is given even in immunosuppressed patients. Source
• Varicella zoster vaccine is a live attenuated vaccine. Source This is safe to give to close contacts of immunosuppressed patients.

Zoster vaccine is recommended for persons 60 years of age or older. This vaccine is similar to the varicella vaccine, except that the titer of virus is ~14-fold higher. The vaccine is about 50% protective in preventing zoster and 66% effective in preventing postherpetic neuralgia. - ScienceDirect snippet

VARICELLA ZOSTER = VIRUS
HERPES ZOSTER = SHINGLES

• A vaccine for Dengue is available! Source

Meningococcal vaccination

Neisseria meningitides is on of the few gram -ve cocci that we have to worry about. Source
They are commensals in the throad of upto 10% of people.
It is spread by close contact with sharing of respiratory or throat secretions.
In some people, risk factors such as predispose to infection.

1. Children < 1 year old
2. Adolescents
3. Elderly (> 65 years old)
4. Comorbidities - Complement defiencies, Asplenia, HIV infection

When a patient gets Meningococcal infection, close contacts should receive prophylaxis. (Drinking from the same bottle, smoking the same cigarette, sharing utensils etc. does not constitute close contact).

The risk of developing the disease for household contacts exposed to patients who have sporadic meningococcal disease was estimated to be 4:1000 exposed people, which is 500 to 800 times greater than the risk for the total population
Source

Neisseria meningitidis is unique among major causes of bacterial meningitis for its ability to cause endemic and epidemic disease. Serogroup A is the commonest cause of large epidemics. Serogroup C causes endemic disease Source

1. Because close contacts are at risk of bacterial transmission
2. because the complications of infection are serious

There are 3 types of vaccines

1. meningogoccal polysaccharide vaccine - poor immunogenecity in children < 5 years old.
2. Conjugate vaccine - meningococcal antigens are conjugated to tetanus toxoid to increase immunogenicity
3. Meningogoccal B protein vaccine - Approved in 2013 in UK. Good immunogenicity but no extensive data.

Vaccination is recommended only for persons with specific high risk conditions including complement deficiency, anatomic or functional asplenia or for those who have had contacts with infected patients.

Vaccination is used for close contacts of patients with meningococcal disease due to A, C, Y, or W135 serogroups, to prevent secondary cases.- MedScape

Treatment:
Rifampicin, ciprofloxacin and ceftriaxone are effective in treatment of N. meningitides infection.

Hypertensive emergency

Hypertensive emergency = hypertension (usually SBP > 180 / DPB > 120) with associated end organ damage.
Otherwise, it's just asymptomatic hypertension.

[!TIP] Need to exclude cause of secondary hypertension
Secondary causes of hypertension are more common in patients who have a hypertensive emergency compared with other hypertensive populations.

Mangement targets:

Aim to reduce MAP

• by 10-20% in the first hour.
• 5 - 15% over the next 23 hours.
  
  BP should not be lowered too rapidly as this risks ischemia of vascular beds which have adapted to hypertension.

Exceptions to normal BP lowering goals

1. Ischemic stroke -
   1. If reperfusion candidate - 185/110
   2. Not reperfusion candidate - 220 / 120
2. Aortic dissection - rapid lowering within 20 minutes to SBP of 100 - 120
3. Haemorrhagic stroke -
   1. Patient presents with SBP of 150 - 220 -> lower SBP to 140 within 1 hour
   2. Presents with SBP > 220 -> rapid lowering to SBP = 220; then lowering to SBP = 140 over several hours.

Drugs used in management of hypertensive emergency

Follicular cells : Papillary, follicular and anaplastic CA.
Parafollicular cells : Medullary CA.

Differentiated thyroid cancers

[!INFO] Hot nodules are almost always noncancerous

• Multifocality is a common pathological feature of PTC.
• Papillary carcinoma is a slow-growing tumor (has good prognosis) that arises from the thyroxine (T4)- and thyroglobulin-producing follicular cells of the thyroid.
• The cancer cells are TSH sensitive and take up iodine. They produce thyroglobulin in response to TSH stimulation
• Papillary CAs form non functional nodules. - Cold on scintigraphy.
• Histology: Unencapsulated; Consist of neoplastic epithelium growing on fibro vascular cores.
• jj
• Ability to invade adjacent lymphatics is a key feature.
• They tend to metastasize to the cervical lymph nodes.
• Haematogenous spread is rare but most common distant metastasis is to the lung.
• Factors which make a papillary CA high risk : Hx of head and neck radiation, male sex, age < 18 or > 55, + other obvious ones.

They arise from the follicular cells of the thyroid. The neoplastic cells are TSH sensitive as well, taking up iodine and producing thyroglobulin—a feature that is exploited diagnostically and therapeutically
Hürthle cell carcinoma is a variant of follicular carcinoma and makes up 2-3% of all thyroid malignancies

Osteoblastic:

Regarding prostate CA:
Pathologic fractures do occur, although they are generally less frequent than in cancers with predominantly osteolytic disease
Source

Source: CVS physiology website.
| presentation | Abdominal pain + perianal disease. (although colonic disease can cause PR bleeding) | GI bleeding |
| Pathology | Transmural involvement(+) (wall to serosa), Granulomas (+) | mucosal and submucosal inflammation |

Immunoglobulin / antibody classes

Neurocysticercosis

#2022BSQ Q5

[!TIP] Mnemonic :"Solium polium" - solium = pork tapeworm.

ONLY TAENIA SAGINATA causes CYSTICERCOSIS.
Probably the most common parasitic infection of the CNS.
Pigs are the usual intermediate host, Humans are the definitive host.

cysticercosis results from humans acting as accidental intermediate hosts for the parasite

[!INFO] Humans eat pig meat -> taeniasis, Humans eat pig poop -> cysticercosis
Ingesting uncooked pork -> ingestion of cysts in pig muscle -> intestinal tape worm infection in the human.
Ingesting eggs in faeces from infected human -> cysticercosis -> possible neurocysticercosis.
In cysticercosis, eggs hatch into larva which migrate through the host body into various tissues.

Now found that most infections are asymptomatic. However, people infected with cysticercosis usually present due to the neurological symptoms.
Seizures are very common.
Diagnosis: Combintion of imaging and serology are required because there are situations in which only one of the two modalities will show positive results.
Imaging : MRI or CT, Serology: Immunoblot / enzyme linked assasy
Treatment:
Treatment of neurological symptoms with anticonvulsants, reducing cerebral oedema, intracranial pressure etc is the main concern.
Then, cysts are treated if required.
Calcified cysts are dead; antihelminthic therapy won't benefit the patient.
Live cysts: Antihelminthing treatment must be combimed with steroid which penetrates the BBB (Dexamethasone) to lessen the inflammatory response elicited following death of the parasite.

Granulomatous disease

Histologic pattern of chronic inflammation.
The particular pattern can suggestive of a particular disease

monocytes in blood -> become macrophages in tissue (aka histiocytes)
histiocyte = tissue macrophage

[!INFO] Granuloma formation: Overview
Granulomas are formed when individual macrophages can't eliminate an antigen.
Then antigen presenting cells in the tissue recruit more macrophages from the circulation into the tissue.
Macrophages all clump around the antigen forming a granuloma.
The macrophages undergo a process called epithelialization where they take on the appearance of epithelial cells.
There membranes beging to interdigitate and the nuclei swell.
Some of the macrophages will fuse to form Langhans giant cells.
The structure of the granuloma differs based on the triggering antigen.
In Tuberculosis, interferon gamma is a mediator of granuloma formation.
Other mediators like TNF-alpha are important in the formation of granulomas.

Metastasis in neoplasia

#2022BSQ Q2

Routes of malignant spread

1. Seedingof body cavities : Typical of ovarian CA
2. Lymphatic spread : more typical or carcinoma
3. Haematogenous spread: more typical or sarcoma.
   1. Arteries are less easily penetrated than veins. Mets occur along venous drainage.
   2. All portal drainage goes to the liver; all caval blood flows to the lung -> these capillary beds are the main sites of metastasis in haematogenous metastasis.
4. Thyroid and prostate CA metastasize via the paravertebral plexus -> vertebral metastases.
   1. bone metastases are more frequent in follicular and medullary thyroid cancers
5. Renal and hepatic CA like to grown inside veins:
   1. Renal - renal veins and IVC
   2. Liver hepatic veins and IVC
6. Path of venous drainage alone doesn't account for the distribution of particular metastatic tumours; Some tumours have a propensity to metastasize to particular organs. This may be due to chemoattraction or expression of tissue specific adhesion molelcules by tumour cells.
   1. prostatic carcinoma preferentially spreads to bone,
   2. bronchogenic carcinomas tend to involve the adrenals
   3. and the brain, and neuroblastomas spread to the liver and bones.

Brain tumours

Primary brain tumours are either

1. Glial tumours - airising from glial cells
2. Non glial - arising from everything else; nerves, blood vessels, glands etc.

Thyroid cancer

Source:Medscape


Follicular cells : Papillary, follicular and anaplastic CA.
Parafollicular C cells : Medullary CA. (C cells are neuroendocrine cells and they produce calcitonin).

Differentiated thyroid cancers

[!INFO] Hot nodules are almost always noncancerous
However, the majority of thyroid nodules scanned are (Approximately 95 percent) are cold**.
Most cold nodules are due to benign processes (>90%)
Cold nodules have an approximately 5% risk of being cancerous.
However, HOT nodules are almost never cancerous.

Both papillary and follicular CA are 3 times commoner in women.
Follicular develops at an older age.

Thyroglobulin is produced by differentiated thyroid CA. It can be used as a marker of recurrent after total thyroid ablation.

Papillary CA:

• Multifocality is a common pathological feature of PTC.
• Papillary carcinoma is a slow-growing tumor (has good prognosis) that arises from the thyroxine (T4)- and thyroglobulin-producing follicular cells of the thyroid.
• The cancer cells are TSH sensitive and take up iodine. They produce thyroglobulin in response to TSH stimulation
• Papillary CAs form non functional nodules. - Cold on scintigraphy.
• Histology: Unencapsulated; Consist of neoplastic epithelium growing on fibro vascular cores.
• Special nuclear features : emtpy nuclei ('orphan annie')
• Ability to invade adjacent lymphatics is a key feature.
• They tend to metastasize to the cervical lymph nodes.
• Haematogenous spread is rare but most common distant metastasis is to the lung.
• Factors which make a papillary CA high risk : Hx of head and neck radiation, male sex, age < 18 or > 55, + other obvious ones.

Follicular CA

Are also usually cold nodules on radioiodine scan.
Commoner in iodine deficient areas.

Histology: encapsulated.
Follicular cells have a solid, trabercular or follicular growth pattern.
No characteristic nuclear features.
No special nuclear features.
Differentiated from benign adenomas by

1. capsular invasion
2. vascular invasion

They arise from the follicular cells of the thyroid. The neoplastic cells are TSH sensitive as well, taking up iodine and producing thyroglobulin—a feature that is exploited diagnostically and therapeutically

Follicular carcinomas have less tendency for local metz (nodes) but higher risk of distant mets.

Distant mets for both types occur to lung and bone.

Hurthle Cell carcinoma

Hürthle cell carcinoma is a rare, more agrressive variant of follicular carcinoma. 5 year survival is 50 - 60%.
Makes up 2-3% of all thyroid malignancies.
Composed of distinct looking polygonal cells with acidophillic cytoplasm.
Associated with RAS mutation and RET/PTC oncogene.

Medullary thyroid Cancer.(MTC)

2-3% of thyroid CA.
They are associated with familial MTC (FMTC) syndromes.
So much so that there is a clinical distinction between identification of patient familial MTC and diagnosis a new sporadic MTC.

Parafollicular C cells produce calcitonin -> elevated calcitonin is diagnostic of MTC.
Inheritance of all familial forms of MTC and MEN2 are #autosomalDominant .
RET proto-oncogene mutations are seen in all MTC syndromes.

Familial cases are multifocal and bilateral.
Sporadic cases are unifolcal.

Histology:
unencapsulated.
Focal calcifications are present.
Characteristic depostion of amyloid is seen in the tumour. <- A unique features in thyroid malignancy.
C cell hyperplasia is unique to familial cases.

Treatment:
Lymph node metastasis is common.
Total thyroidectomy with lymph node clearance is done.
Prophylactic thyroidectomy is done in children diganosed with MEN2 syndromes.

FMTC syndromes:

1. MEN2A - pheochromocytoma, hyperparathyroidism.
2. MEN2B - MTC, phaechromocytoma, marfanoid habitus and galngioneuromatosis.
3. FMTC - only MTC.

In treatment of MEN, to avoid intra op hypertension, resection of pheochromocytoma should be done before MTC resection.

Anapalstic thyroid CA

[!WARNING] A very, very bad cancer!
It is rare but has the worst prognosis of all thyroid CAs.
Occurs in older adults (60-70) -> older adult with a thyroid nodule could have a dangerous thyroid CA.
1 year survival is a dismal 20%. Median survival is 5-6 months.

Anaplastic CA grows rapidly. Many patients present with local invasion (unresectable tumours) or cervial lymph node metastasis.

On histology, the tumour retains feature so epithelial cells (presence of desmosomes) but there are large areas of necrosis and bleeding. There is high mitotic activity.

Bone tumours

• In adults, bone mets are far more common than primary bone tumours.

• Bone is the 3rd commonest site of metastatis next to Lung and liver.

• Prostate and breast cancer (BC) are responsible for the majority of the skeletal metastases (up to 70%).

• Other sources of bone mets : thyroid, renal cell carcinoma, lung cancer, melanoma

Bone metastasis

Bone mets are commonest in spine, pelvis and thigh.

Osteolytic :

1. Multiple myeloma
2. RCC
3. melanoma
4. NSCLC
5. Non Hodgkin Lymphoma
6. thyroid cancer
7. Breast cancer

Osteoblastic:

1. prostate cancer,
2. carcinoid,
3. small cell lung cancer,
4. Hodgkin lymphoma
5. medulloblastoma.

Ignore breast in this list!

Regarding prostate CA:
Pathologic fractures do occur, although they are generally less frequent than in cancers with predominantly osteolytic disease
Source

Multiple myeloma – The classic bone lesions in multiple myeloma are purely osteolytic due to increased bone destruction and suppressed bone formation.

Prostate cancer – Males with bone metastases from prostate cancer predominantly have osteoblastic (aka sclerotic) lesions with increased numbers of irregular bone trabeculae. Simultaneously, osteoclastic action is also increased.

Breast cancer - The great majority of breast CA produces osteolytic bone lesions, osteoblastic areas are also usually present

Renal cancer also commonly spreads to bone.

Atherosclerosis

#2022BSQ Q8
Plaques are raised lesions in the blood vessel.
Filled with cholesterol and cholesterol esters.

Overview of atherosclerosis

Atherosclerosis requires two factors

1. Endothelial dysfunction
   1. Involving altered gene expression (eg. incr. adhesion molecules) and increased permeability of endothelial cells.
   2. This allows migration of blood monocytes into the intima where they become macrophages.
2. Increased lipids in the blood
   1. Cholesterol and it's esters are found inside plaques. They stimulate chronic inflammation in the intim in the presence of macrophages.

Anything that exacerbates these two factors will promote atherogenesis.

1. Endothelial damage and dysfunction
   1. Smoking, hypertension, flow turbulence, some infection, ?toxins and drugs
2. Hyperlipidaemia
   1. Any condition increases blood lipid levels ?Which lipids exactly - not HDL.

In the presence of lipids within the intima, macrophages become activated. When they engulf lipids, they become foam cells.
Cytokines secreted by macrophages stimulate altered function and growth of smooth muscle cells of the media.
Smooth muscle cells proliferate and take on fibroblastic roles.
Smooth muscles + collagen produced by them form the fibrous cap of the plaque.

Plaques can

1. obstruct vessels
2. rupture -> thrombosis
3. weaken the media -> aneurysms

Factors which make a plaque unstable:

1. Thin fibrous cap
2. Increased foam cells
3. Increased lipid content etc.

Pancreatic physiology

#2022BSQ Q24

Secretin and CCK are endocrine hormones.
Secretin - role is to neutralize stomach effluent

• peptide hormone
• produced by S cells of duodenum and brain
• inhibits gastrin release -> to reduce stomach acid production
• Stimulates pancreatic secretion of fluid and bicarbonate
  Cholecystokinin - promote pancreatic enzyme secretion, and gall bladder contraction.

Secretin stimulation test: Although secreting physiologically inhibits gastrin secretion, in the presence of a gastrinoma, secretin paradoxically increases gastrin secretion. This is the basis of the secretin stimulation test for gastrinoma.

Selected gastrointestinal regulatory peptides

#2022BSQ Q24

See table 32.4 K and C.
Secretin glucagon family
Vasoactive intestinal peptide (VIP) -> Secreted by enteric NERVES -> Neurotransmitter, Stimulates insulin release, splanchnic vasolidation and intestinal secretion of water and electrolytes; also relaxes smooth muscles, including the lower esophageal sphincter and colon

Glucose dependent insulinotropic polypeptide - GIP - - From duodenum, gastric antrum and ileum - stimulated by intraduodenal glucose -> incretin effect. (produced by K cells)

GLP-1 - The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, to limit postprandial glucose rise. Secreted by L cells in the ileum and colon.

Humans have almost no L cells proximal to the ligament of treitz (i.e in the duodenum) Source

Secretion is likely triggered by glucose in the duodenum as well as the rest of the gut as well. Source

GLP-1 physiology

Source
Only a small percentage of the produced GLP-1 reaches the liver and systemic circulation because of the action of DPP-IV.

[!TIP] All of these hormones generally cause changes which promote digestion and absorption except for somatostatin

Bilirubin physiology and elevations

CT

[!INFO] Significance of active conjugated bilirubin secretion from hepatocytes
The active secretion of cojugated bilirugin into bile cannaliculi is rate limiting. But uptake of unconjugated bilirubin is very efficient.
Therefore, hepatocytes near the supplying veins will take up all the unconjugated bilirubin but may not be able to excrete all of it into the bile. Therefore, they reexcrete it into the sinusoids so that down stream hepatocytes can reuptake this conjugated bilirubin and help to excrete it into the bile canalliculi.
I.e more hepatocytes are recruited for excretion.
The transport proteins requried for reabsorption are affected in Rotor syndrome -> leads to conjugated and unconjugated hyperbilirubinaemia.

Complement system overview

Causes of increased CPK

#2022BSQ Q31
CPK = CK.
Creatine Kinase is a catalyst for the formation of ATP from ADP via transfer of phosphate from creatine phosphate (which is an energy reservoir for muscle.
It is a very good indicator of muscle breakdown and it's progression.
CPK is eleminated by the Reticuloendothelial system. Serum level isn't elevated in kidney disease.

3 isoforms

• Skeletal muscle - 99% CK MM

• CK-MB = Usually in cardiac muscle. Can also be elevated in elite athletes and normal people after strenuous exercise (i.e can produce false +ve for MI)

• CK is usually elevated in myopathies. => there are different types of myopathies

  • Inflammatory myopathies - polymyositis / dermatomyositis
  • Drugs - colchicine (gout), antimalarials, statins, alcohol
  • Metabolic myopathies - carnitine palmitoyltransferase deficiency, Muscle phosphorylase deficiency (McArdle's disease)
    • McArdles disease - Autosomal recessive, exercise intolerance in childhood followed by cramps and myoglobinuria
  • Endocrine myopathies - hypothyroidism, acromegaly
  • Periodic paralyses - hours to days of muscle weakness with sharp rises of CPK; due to muscle membrane refractoriness secondary to ion shifts.
  • Neuroleptic malignant syndrome
  • Malignant hyperthermia - usually follows use of anaesthetic agents.

• Can also be elevated in a few non myopathic conditions

  • Exercise
  • Iatrogenic muscle injury
  • motor neuron disease
  • Asymptomatic elevation in CK

Urine cultures

We went to get urine samples which contain bacteria which have managed to enter the bladder. (bacteria colonize the distal urethra and genital mucosa)
Theoretical best sample is first voided urine of the day as bacteria have had time to multiply overnight and it is also the most concentrated sample.
Suprapubic taps should yield sterile urine in a healthy patient.

Prostatic massage should be done prior to urine sample correction in suspected if chronic bacterial prostatis is suspected. Massage should be avoided in acute bacterial prostatits -> risk of bactiraemia!

Sample is cooled until it is send to the lab to prevent bacterial multiplication affecting the colony count.

Urine microscopye

pyuria

8 cells / microL = 2-5 cells per High power Field.
Very high associated with urinary infection.

• bacteuria without pyuria -> usually means colonization rather than infection. (unless of course, patient is symptomatic)

White blood cell casts - renal infection = could be pyelonephritis.

Causes of sterile pyuria:

• False -ve for bacteria
  • Contamination with antiseptic
  • Atypical pathogens - Chlamydia, Ureaplasma urealyticum, or tuberculosis
• False +ve for leukocytes
  • Contamination with vaginal leukocytes
  • Chronic intersitial nephritis - omeprazole is a cause.
  • Nephrolithiasis
  • Uroepithial tumour
  • Intrabdominal inflammation adjacent to the bladder

Cardiac action potentials

Source: CVS physiology website.

Electrolyte effects on ECG

Hyperkalemia
EKG changes progress from peaked T-waves to widened QRS and eventually to ventricular tachycardia, fibrillation or pulseless electrical activity arrest.  These progressive changes can correlate with rising potassium levels. For example, peaked T waves might correspond with a potassium level of approximately 6 mmol/L, whereas cardiac arrest generally occurs at higher levels.

Hypokalemia
EKG changes can include increased amplitude and width of P wave, T wave flattening and inversion, prominent U waves and apparent long QT intervals due to merging of the T and U wave.
The U-wave is a deflection following the T wave. Hypokalemia causes enlarged and prominent T waves on the EKG. Potassium levels that are critically low (<1.7 mmol/L) can lead to torsades de pointes or“twisting of the points”, a polymorphic ventricular tachycardia.

Hypercalcaemia
The most common EKG finding associated with hypercalcemia is shortening of the QT interval. In severe cases, Osborn or J waves might be seen or ventricular fibrillation might ensue. Recognition of these EKG findings can prompt urgent treatment.

Hypocalcemia
The most common finding on EKG in patients with hypocalcemia is a prolonged QT interval.

https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.105.166563

doi.org/10.1016/0002-9149(63)90255-8

Hypermagnesaemia

Tumour markers

[!TIP] GPT answer:
Certainly! Here is a list of common tumor markers and the tumors they are commonly associated with:

1. Prostate-Specific Antigen (PSA) - Prostate cancer
2. Carcinoembryonic Antigen (CEA) - Colorectal cancer, pancreatic cancer, lung cancer
3. Alpha-fetoprotein (AFP) - Liver cancer, germ cell tumors, particularly testicular cancer
4. CA-125 - Ovarian cancer
5. CA 19-9 - Pancreatic cancer, colorectal cancer
6. CA 15-3 - Breast cancer
7. CA 27-29 - Breast cancer
8. Human Chorionic Gonadotropin (hCG) - Germ cell tumors, particularly testicular cancer, ovarian cancer, ?lung CA
9. Calcitonin - Medullary thyroid cancer
10. Thyroglobulin - Thyroid cancer (papillary and follicular)
11. Neuron-Specific Enolase (NSE) - Neuroendocrine tumors, small cell lung cancer
12. Chromogranin A - Neuroendocrine tumors
13. S-100 Protein - Melanoma, neuroendocrine tumors
14. Human Epidermal Growth Factor Receptor 2 (HER2) - Breast cancer, gastric cancer
15. Epidermal Growth Factor Receptor (EGFR) - Non-small cell lung cancer, colorectal cancer
16. 5 HIA - carcinoid tumour
17. Carcinoid tumors are of neuroendocrine origin and derived from primitive stem cells in the gut wall, especially the appendix.

BRCA1 and BRCA2 - breast and ovarian cancer.

Inflammatory bowel disease

[!TIP] A great summary!
Source

[!INFO] Differentiation of disease is vital to determine the potential effectiveness of surgery!
resection is curative in UC but disease recurs after resection in Crohn's

Peak incidence for both is between 15-30 years. Buy disease can occur at any age.

Extraintestinal manifestations of Crohn's disease

1. Migratory arthitis - appendicular skeleton. Parallels intestinal disease. Treatment of intestinal disease resolves arthritis.
2. Perichonlangitis - seen on ERCP or MRCP.
3. Kidney stones
4. Bowel inflammation -> ureteric obstruction and hydronephrosis
5. Fistulas

Ileal resection can cause bile acid malabsorption -> diarrhoea.

Immunoglobulin / antibody classes

#2022BSQ BSQ Q49

Source

Insulin

#2022BSQ Q40

Sources of insulin

Animal based : not commonly used.
Bovine insulin differs from human by 3 amino acids, porcine by 1 amino acid.

Pharmacokinetics

Regular insulin and NPH insulin are considered older insulins.
Their time to peak and duration of action don't mimic physiologic secretion.

(U-100) denotes the usual concentration (100 U/ml).

Regular insulin

Duration: Short acting.
Controls post prandial glucose rise.
Same AA sequence as human insulin.
Bound to Zinc.
Hexamers must be converted to dimers and monomer before absorption -> leads to a delay in peak concentrations-> should be given 30 minuted before meals.
Duration of action tends to exceede duration of post prandial glucose rise -> risk of hypoglycaemia.

NPH insulin

Duration: Intermediate.
Suspension of human insulin, protamine and zinc. -> delays release of insulin into blood, also longer time to peak.
Patient must eat after the morning dose is given, to avoid hypoglycaemia.

Delivery :

mix immediately before injection and given at room temperature.
NPH insulin is a cloudy solution.
Can be mixed with regular or rapid acting insulins in the syringe.
Always draw up the regular(clear) insulin first to avoid contaminating the regular insulin with isophane insulin, thereby altering its pharmacokinetics.

U-500 insulin

Not regularly used nowadays, partly because of the advent of DPP-4 inhibitors.

Insulin analogs

made by recombinant DNA technology.
Subsitution of amino acids produces rapid acting and long acting analogs.

Rapid acting insulins

Lispro, aspart, glulisine (and faster aspart, lipro-aabc)
Duration: (very short) duration and rapid onset

modifications were made in the insulin molecule to prevent it from forming hexamers or polymers that slow absorption and delay action

Insulin aspart- substitution of aspartic acid for proline at position B28.

Insulin lispro is identical to human regular insulin except for a lysine and proline at positions B28 and B29.

Insulin glulisine has a lysine and glutamic acid at positions B3 and B29 respectively.

Rapid acting insulins are move convenient.
U-200 lispro and U-200 lispro-aabc, are high concentration preparations which have some niche use cases.

Basal insulin analogs

Determir

Insulin detemir – Detemir is an acylated insulin; the fatty acid side chain allows reversible albumin binding as well as concentration-dependent self-association (ie, formation of dihexamers) that results in prolongation of action.
Determir is much less potent - so it is formulated in a 4:1 ratio. (1 Unit of determir contains four times as many insulin molecules as any other preparation of insulin)
Can't mix with rapid acting insulins.

Glargine

Glargine is identical to human insulin except for a substitution of glycine for asparagine in position A21 and by the addition of two arginine molecules to the amino terminus.

After subcutaneous administration, glargine precipitates in the tissue, forming hexamers, which delays absorption and prolongs duration of action.

Glargine, which is in an acidic solution, cannot be mixed with rapid-acting insulins, as the kinetics of both the glargine and rapid-acting insulin will be altered

Glargine has less nocturnal hypoglycemia than NPH insulin

Duration of action : 24 hours but some may need twice daily dosing as half life is 12 hours. Unlike glargine, it has a small peak in it's concentration profile.

Higher concentration preparations of glargine (U-300) have an even flatter concentration curve with lower hypoglycaemic effect.

Degludec

form multimers from which monomers are release-> even longer duration of action.
Can mix with rapid acting insulins.

Determinants of insulin efficacy

• Site of injection - Limbs are faster than abdomen. (muscle-> increased blood flow)

  • 

  NPH insulin - leg or buttock preferred for moderate rate of absorption.
  Pre meal regular insulin - abdominal wall preferred for rapid absorption.

The absorption of the long-acting basal insulin analogs, glargine and degludec, do not appear to be significantly influenced by injection site

• Technique
  • Too shallow: intradermal injection that is not well absorbed.
  • Too deep: intramuscular -> rapid absorption
  • 4mm neele - can give perpendicular injection
  • 6mm needle - give at 45 degrees.
  • Rotate sites to avoid lipohypertrophy.
  • Injection through clothes won't cause dlivery problems but it means that skin cannot be inspected before injection -> not recommended.
• Size of the depot
  • Larger depot size - less overall absorption and more variability in absorption.
• subcutaneous blood flow
  • reduced by smoking
  • Increased by exercise and hot baths.
  • Variations not as significant with long acting insulins.

Types of hypersensitivity

#2022BSQ Q48

Hypersensitivity reactions refer to undesirable responses produced by the normal immune system - Source

[!INFO] Mnemonic
Type III - 3rd letter in alphabet - C for immune complexes.
[[Toxicology#Serum sickness]]

[!TIP] Hypersensitivity Vs Autoimmune disease
Hypersensitivity is an abnormal immune response to a harmless stimulus. When the 'stimulus' is a self antigen, we call it autoimmunity.

Autoimmune diseases can be classified in the same way as hypersensitivity conditions. but IgE is not involved in autoimmunity.
so in the table[[2022 November SBR]] below, there is no "type I" in the autoimmune categories

Autoimmune diseases examples

Autoimmune diseases caused by antigens against cell surface receptors: [[moreAutoimmuneDiseases.png]]

Infectious diarrhoea

#2022BSQ Q54

Diarrhoea in resource rich settings

• can be studied under inflammatory diarrhoeal causes and watery diarrhoeal causes.
  See mnemonics below:
  [[diarrhoeaInResourceRichSettings.png]] <- A good table!

[!TIP] Water diarrhoea
Same day:

1. Norovirus
2. clostridium perfringens
3. possibly listeria (pregnancy, immunosuppression, extremes of age)

Next day:

1. E coli - enteroroxigenic
2. most other viruses - (1-3 days) diarrhoea in children, immunocompromised adults

Same week

1. Cyclospora

Weeks later

1. Giardia 1 to 2 weeks later - day care, swimming pools, travel / camping.
2. Cryptosporidium 2-28 days (upto 1 month after) - Associated with day care centers, swimming pools.

[!TIP] Mnemonics: inflammatory diarrhoea
Fever, mucoid or bloody stools show infective diarrhoea:
"Can't Assume Everyone's Your Very Special Sidekick"

Let's break it down:

1. "Can't" - Campylobacter
2. "Assume" - Amoebiasis
3. "Everyone's" - E. coli
4. "Your" - Yersinia
5. "Very" - Vibrio parahaemolyticus
6. "Special" - Salmonella
7. "Sidekick" - Shigella

Most of these have P-incu of 1-3 days. But, entamoeba - much longer- 1 to 3 weeks, yersinia - slightly longer- 4-6 days, E-coli 1-8 days.

Diarrhoea in resource poor settings

Epidemic diarrhoea

Main two pathogens of epidemic diarrhoea

1. Cholera (secretory rice water diarrhoea) [[Misc infectious diseases#Cholera]]
2. Shigella dysenteriae - SD1 serotype. (inflammatory diarrhoea - blood + mucous)

Non epidemic diarrhoea

Commonest causes of non epidemic watery diarrhoea - E. coli.

[!TIP] mnemonic
Acute bloody diarrhoea
$$
\Large{C^1S^2E^3}
$$

Commonest cause of non epidemic bloody diarrhoea - shigella flexneri (not dysenteriae)

• other causes of acute bloody diarrhoea
  • Campylobacter
  • Enteroinvasive E coli
  • Enterhemorrhagic E coli
  • Entamoeba histolytica
  • [[Misc infectious diseases#Schistosoma|Schistosoma mansoni]]

Enterobiasis

Pin worm.
Humans are considered the only host for E. vermicularis
Infection is commonest in children and institutionalised people.
Treatment is easy; reinfection is also easy.
Commonest symptom: itching in the perianal area, possible with excoriation and seconday bacterial infection.
Perianal itching / scratching contributes to faeco-oral transmission of the parasite.
Infection of the female genital tract can occur. Can cause abdominal pain mimicking appendicitis.
Treatment: Albendazole, mebendazole

Strongyloidosis

Strongyloides stercoralis : thread worm
First discovered in french troops returning from vietnam in the 19th century who developed chronic diarrhoea.
Infective stage : Filariform larva: -> penetrates intact skin.

[!INFO] How to understand the life cycle;
parasite has a free living cycle and parasitic cycle
Eggs can be deposited a) In the host intestine and b) in the environment.
Eggs always produce rhabditiform larvae.
Eggs -> rhabditiform larvae -> filariform larvae. (Infective stage) (autoinfection or otherwise).
If excreted with stool, rahbditiform larvae can go on to develop into adult sexual stages which produce more eggs in the free living cycle.

Female Adult worm (who live embedded in the submucosa of the small intestine) lays eggs.

It has been thought that the L3 larvae migrate via the bloodstream and lymphatics to the lungs, where they are eventually coughed up and swallowed. However, L3 larvae appear capable of migrating to the intestine via alternate routes (e.g. through abdominal viscera or connective tissue)

Symptoms:

Respiratory : Dry cough - about 1 week after infection
Abdominal pain, bloating, intermittent constipation and diarrhoea - about 3 weeks or later after infeciton (due to infection of the small intestine)
Skin: Itchy rash at site of entry; recurrent red rash along thighs and buttocks. - Larva currens (pathognomonic of Strongyloidiasis).
Disseminated life threatening infection can occur in immunosuppressed people.
Eosinophilia(+)

Management:

Ivermectin has been shown to be superior to albendazole.

Ivermectin: binds selectively and with high affinity to glutamate-gated chloride ion channels in invertebrate muscle and nerve cells of microfilaria.

Albendazole and other similar drugs inhibit the beta tubulin of worms (intracellular cytoplasmic structural protein) -> immobilization and death.

Skull base fracture

#2022BSQ Q51
Skull base fracture and associated injuries; Source
NCBI article <- good link
Cranial nerve injuries: Page 1079 of Moore's clinical anatomy.

Sjogren syndrome

#2022GM Q14
Pathogenesis: Autoimmune disease affecting exocrine glands.

In most cases, Sjogren syndrome is only 'irritating' and not dangerous.

Can occur as a primary disorder or secondary to another rheumatic disease.

Symptoms are classified mainly as

1. Exocrine gland symptoms
   1. Predominant symptoms of Sjogren's syndrome are
      1. oral dryness (affects salivary glands)
      2. and dry eyes. - assessed by Schirmer test < 5mm/min.
2. Extra glandular symptoms
   1. Skin :
      1. Xerosis (dryness)
      2. Raynaud's phenomenon
      3. Cutaneous vasculitis: Palpable purpura is the commonest manifestation.
   2. Muskuloskelatal: Arthralgria, myopathy, fibromyalgia.
   3. Associated with autoimmune thyroiditis.
   4. Lungs - interstitial lung disease; upper and small airway involvement; Patients have cough and dyspnoea.
   5. Peripheral neuropathy
   6. Depression / mood changes/ mild cognitive impairment (maybe due to poor sleep)
   7. Mild anaemia and leukopenia
   8. Other autoimmine diseases
      1. Myasthenia gravis
      2. Autoimmune hepatitis/ pancreatitis.
   9. Increased incidence of Non Hogdkins B lymphoma.
   10. Can cause renal involvement - hypokalemia is common secondary to distal RTA with K+ wasting.
   11. Rare complication of Sjogren syndrome during pregnancy : congenital heart block.

Spectrum of disease:

Mild disease : just dry eyes and mouth; Requires diagnostic criteria to be fullfilled to diagnose SjD.

Severe disease:
A severely affected patient may have florid salivary gland enlargement, adenopathy, antibodies to the Ro/SSA and La/SSB antigens, cryoglobulinemia, hypocomplementemia, a propensity to develop non-Hodgkin lymphoma, and other extraglandular disease manifestations.

90% are positive for Rheumatoid factors: Kumar and Clark

Epidemiology: Most Commonly occurs in women aged 50-60 years old.

Associated conditions

Keratoconjuntivis sicca - term for the occular manifestations of Sojgrens.
Mikulicz syndrome: Parotid and lacrimal gland enlargement; Sojgren's disease is one possible cause of this.

Diagnostic criteria:

Biopsy showing focal lymphocytic infitrate of labial salivary glands. Termed Focal lymphocytic sialadenitis.
Objective test: Focal lymphocytic sialadenitis score >= 1;

Anti Ro/SSA and anti La / SSB positivity suggests Sojgren's disease.

Background of systemic autoimmune disease. -
The most common associations are SLE and Rheumatoid arthritis.

Pathogenesis of ascites in Cirrhocis

Several haemodyanic and vascular changes occur which contribute to the formation of cirrhocis.

Vascular:

• Decreased peripheral resistance (and reduced arterial pressure)
  • (most apparent in the splanchnic circulation)
• Increased circulatory volume
• Increased cardiac output (and tachycardia)
• Increased portal blood flow
• I.e Hyperdynamic circulation is present.
  but, with
• Decreased renal perfusion (kidneys compensate by increasing their production of prostacyclin - a vasodilator. This effect is lost in patients with hepatorenal syndrome and can be inhibited iatrogenically by NSAIDS -> both causing a ==disastrous== fall in renal plasma flow!)

Multiple mediators have been studied as sources of the systemic vasolidation but the most important one seems to be increased NO synthesis.

inhibition of synthesis of NO in rats restores normal arterial pressure.

? cause for increased NO
Portal hypertension -> increased portosystemic shunting -> decreased hepatic clearance of bacterial toxins / DNA absorbed from GI tract.

mediated by vascular changes:
Splanchnic vasodilation
Renal artery vasoconstriction
(and also pulmonary vasodilation)

Ascites: The pathological accumulation of fluid in the peritoneum.
Development of portal hypertension is the first step and is essential for the formation of ascites in cirrhocis.

Older theories of ascities formation : undefill theory and overflow theory. Modern arterial vasodilation hypothesis fits better with data.

Arterial vasodilation theory of ascites formation

A portal pressure >12 mmHg appears to be required for fluid retention
Portal hypertension is not simply due to mechanical obstruction of the portal system. It occurs due to increased flow from the splanchnic arteries.

See hypothesis-highlights on UpToDate

SAAG

#2022GM Q32
Serum 'to' Ascites Albumin gradient

SAAG > 11g/L - low protein in ascitic fluid => Suggest portal hypertension as cause; (i.e transudate)
SAAG < 11g/L - high protein in ascitic fluid (or low serum protein) => Exudate (?malignancy)

Low ascitic fluid protein may increase the risk of SBP as there are no opsonins in the fluid to combat infection.

Liver transplantation

Indications for liver transplantation

1. Acute liver failure of any cause
2. Chronic hepatic failure with Childs grade > C or MELD > 20;
   1. hepatopulmonary syndrome can be reversed by hepatic transplantation.
3. Primary biliary cholangitis
4. Chronic hepatitis B is HBV DNA negative or falling; recurrence of infection is prevented by HBIG and nucleoside analogues.
5. Autoimmune hepatitis
6. Alcoholic
7. Metabolic disorders - haemochromatosis, Wilsons, Alaph a antitrypsin deficiency
8. NASH cirrhocis

Bronchiectasis

#2022GM Q21

Review of airway histology

Respiratory epithelium - ciliated pseudostratified columnar epithelium.

Note the presence of smooth muscle and it's decreasing thickness as the airways become smaller.

Bronchioles - intralobular airways < 1mm in diameter arising roughly after the 10th generation of branching.

Epidemiology

Commoner in women.
Increases with age; marked increase after 60 years.

Pathology

Bronchiectasis is the permanent dilation of bronchi and
bronchioles caused by destruction of the muscle and the
supporting elastic tissue, resulting from or associated with
chronic necrotizing infections. It is not a primary disease
but rather secondary to persisting infection or obstruction
caused by a variety of conditions

Obstructive impairment (ie, reduced or normal FVC, low FEV1, and low FEV1/FVC) is the most frequent finding on spirometry. ;
$$
\LARGE{Obstruction = ↓\frac{FEV_{1}}{FVC}}
$$

Morphology

Usually affects bilateral lower lobes.
Permanent dilation -> small airways are traceable almost upto the pleura. (in normal lungs, they stop about 2 cm short of the pleura)
Chronic inflammatory exudate is seen.
Extensive desquamation of epithelium causing ulceration.
Healing is usually by fibrosis.
Abscesses can form as complications.

Diagnosis:

Clinical and CT:
CT features that are reliable signs of bronchiectasis:

• Airway-to-arterial ratio ≥1.5 (internal airway lumen diameter/adjacent pulmonary artery diameter)
• Lack of tapering of bronchi (tram track appearance)
• Airway visibility within 1 cm of a costal pleural surface or touching the mediastinal pleura

Causes of bronchiectasis and basis of disease

Common causes

Obstruction - tumour, lymph nodes, aspiration etc. <- impaired drainage
Inherited disorders -
Cystic fibrosis <- impaired clearance of mucous
Kartagener syndrome <- Ciliary impairement
Autosomal recessive #autosomal-Recessive
Situs inversus, chronic sinusitis, and bronchiectasis; Underlying pathology is primary ciliary diskinesia. Kartagener Xn is a subset of primary ciliary diskinesia (in which patients may not have situs inversus).
Screening test -> patients have low levels of nasal nitric oxide.

Immunoglobulin deficiencies <- recurrent infection
Necrotizing of suppurative pneumonia - staph aureus or klebsiella <- scarring and impaired clearance; ?exagerrated neutrophil response

Other causes

Young syndrome - similar to CF but no evidence of CF; rare diagnosis nowadays.
Associated with two rheumatic disorders - Sjogren syndrome and Rheumamtoid arthritis.
[[General Medicine 1#Allergic bronchopulmonary aspergillosis|Allergic bronchopulmonary aspergillosis]] - ? central bronchiectasis

Management

Antibiotics for exacerbations
Control of acute bleeding with bronchoscopic local therapy or bronchial artery embolization.
Refractory disease: surgical therapy - ? resection

Immunodeficiency syndromes

Primary immunodeficiencies arise from inborn defects. They usually present in childhood.
Common variable immunodeficiency is an notable exception to this.

Seconday immunodeficiency is far more common (?in adult populations)

• Diabetes mellitus
• Human immunodeficiency virus (HIV) infection
• Cirrhosis
• Nephrotic syndrome
• Other protein-losing states, such as enteropathies, severe exudative skin disease including burn injury, and peritoneal dialysis
• Malnutrition
• Hemoglobinopathy
• Inflammatory bowel disease or rheumatoid arthritis receiving immunosuppressive therapies (particularly tumor necrosis factor [TNF] inhibitors)
• Neurologic disease
• Autoimmune disease
• Splenectomy
• Malignancy
• Radiation therapy
• Immunosuppressive agents, such as glucocorticoids and others
• Immunomodulatory agents, such as rituximab, etanercept, and others

Typical presentations and associated defects in the immune system

Skin infections, in isolation, are not usually indicative of an underlying primary immunodeficiency.
 Recurrent abscess formation in the same anatomic location often arises from a local defect, such as a congenital branchial cleft cyst, pilonidal or urachal cyst, hidradenitis suppurativa, or a retained foreign body.
 Chronic mucocutaneous candidiasis - ussually begins in childhood; associated with several immunodeficiency states; usually doesn't show systemic infection with the fungus.
 Recurrent herpevirus infection / reactivation -> These individuals should be evaluated for underlying T or natural killer (NK) cell dysfunction.
 However, recurrent respiratory tract infections in combination with more serious infections are a classic presentation of antibody deficiencies.
 Isolated urinary tract infections are more suggestive of anatomic defect than immunodeficiency.
 Relapsing, recurrent, and/or progressive enterocolitis due to common enteropathogens, such as Giardia, enteroviruses, cytomegalovirus, and campylobacter, are associated with underlying hypogammaglobulinemia and/or T cell immunodeficiency.
 recurrent Neisseria meningitidis meningitis -> Deficiency of one or more of the terminal complement components (C5, C6, C7, C8, C9) . Low complement levels may be due to either congenital complement deficiency or acquired diseases, such as systemic lupus erythematosus.
 Immunoglobulin deficiency disorders or impaired reticuloendothelial function resulting from splenectomy or hemoglobinopathy are associated with an increased risk of bacteremia and meningitis due to encapsulated pathogens.
 Marked elevation of serum IgE with multisystem infections -> Job syndrome

Amyloidosis

"Amyloid" was meant to describe the starch like properties of the substance. Initially described as "waxy" and "lardaceous".

Subtypes of amyloidosis

There are 18 different types of systemic and 22 localized forms of amyloidosis

The four most common causes of systemic amyloid deposition are

1. AL amyloidosis
2. ATTRwt - wild type transthyretin amyloidosis
3. Hereditary (famliliarl) amyloidosis
4. AA amyloidosis

[!INFO] AL Vs AA : importance of differentiating
AL amyloidosis must be differentiated from other forms of amyloidosis (eg, AA amyloidosis, ATTRmt amyloidosis, and ATTRwt amyloidosis) since the latter are non-neoplastic and will not benefit from chemotherapy.

Other forms of amyloidosis:

• Heritable amyloidosis types
• Organ specific amyloidosis
• Dialysis related amyloidosis

Diagnosis

Histological : Fat pad biopsy (less risk of bleeding)
Organ biopsy is needed if a specific organ is involved.

When congo red stains binds to amyloid protein, it produces apple green birefringence.

Looks similar to DM nephropathy but the staining characteristics are different (DM nephropathy is PAS and silver stain positive)

AL amyloidosis

AL amyloidosis is Associated with plasma cell dyscrasia (multiple myeloma, waldenstrom macroglobulinemia)

Symptoms and signs

There is multisystem amyloid deposition

• Fatigue, non intentional weight loss

• Heavy proteinuria (70%) - nephrotic syndrome

• oedema

• #hepatosplenomegaly (hepatomegaly +/- splenomegaly seen in 70%)

• Cardiomyopathy and heart failure (60%) - thickening of interventricular septum is present / MI due to accumulation of amyloid in coronaries.

  • Cardiomyopathy is common in AL and ATTR but rare in AA amyloidosis

• Neuropathies - carpal tunnel, mixed sensory and motor peripheral neuropathy is a prominent feature in AL amyloidosis. (Symptoms of numbness, paresthesia, and pain are frequent)

• Amyloid infiltration of muscles - macroglossia with scalloping and shoulder pad sign. (also enlarged deltoids)

• Skin - purpura (raccoon eyes with valsalva maneuver is specific), waxy skin, easy bruising.

• Coagulopathy - possibly due to factor X binding of coagulation factors to amyloid.

• GI involvement: gastroparesis, constipation, bacterial overgrowth, malabsorption, and intestinal pseudo-obstruction resulting from *dysmotility

  Criteria for organ involvement

Treatment

Bortezomi based induction
Melphalan
Haematopoietic cell transplantation.

Prognosis

This disorder has a poor long-term prognosis, with cardiac or hepatic failure, and infection being the major causes of death
Earlier detection confers better outcome.

AA amyloidosis

The most common organ affected by AA amyloid is the kidney (approximately 80 percent of patients -> causes nephrotic syndrome.

AA amyloidosis may complicate chronic diseases in which there is ongoing or recurring inflammation, such as rheumatoid arthritis (RA), spondyloarthritis, or inflammatory bowel disease; chronic infections.

Symptoms

SImilar to AL (but cardiomyopathy is rare)
GI involvement: similar to AA amyloidosis

Treatment

In untreated patients, AA (secondary) amyloidosis carries a significant risk of mortality due to end-stage kidney disease, infection, heart failure, bowel perforation, or gastrointestinal bleeding.
Successful treatment of the underlying inflammatory process improves kidney function.

Spondyloarthritis (SpA)

Spondylos = greek for vertebrae

common features

• chronic low back pain
• positivity for HLA B27 antigen (present in 90% of those with AS)
  • (However, there is high background positivity of approx 8% so HLA isn't usually used in diagnosis. )
• radiographic changes in the sacroiliac joints in patients with axial SpA
• and asymmetric (oligo)arthritis, heel enthesitis and dactylitis in patients with peripheral SpA
• uveitis, inflammatory bowel disease, psoriasis, and increased levels of acute phase reactants

Uveitis
The presence of leukocytes in the anterior chamber of the eye is characteristic of anterior uveitis.
The presence of leukocytes in the vitreous humor - intermediate uveitis
Evidence of active chorioretinal inflammation -> posterior uveitis

• Rheumatoid factors negative. (<- Seronegative arthropathies)

characteristic radiographic features

Sacroiliac joint:
sclerosis,
joint space widening, or erosion (fusion in late stages)
syndesmophytes and changes of spondylitis in the spine, which are most often detected in more longstanding disease.

A syndesmophyte is a bony growth originating inside a ligament, commonly seen in the ligaments of the spine, specifically the ligaments in the intervertebral joints leading to fusion of vertebrae.

Inflammatory osteoproliferative lesions in the spine are called syndesmophytes (marginal and non-marginal), and degenerative osteoproliferative lesions are called osteophytes. Syndesmophytes are more vertically oriented than osteophytes.

subtypes of SpA

• Ankylosing spondylitis
• Psoriatic arthritis
• Reactive arthritis
• IBD related arthritis
• And some other types
  • nonradiographic axial SpA (nr-axSpA), peripheral SpA,

#TODO add image of enthesis

Ankylosing spondylitis

#2022GM Q25
#2022GM Q27

Ankylosing = stiffness or fixation of a joint by disease

Affects teens to early 30s, male >> female (5:1).
Pathology: lymphocyte and plasma cell infiltration of the attachments of ligaments. (enthesitis)

Some terminology: not super important

Pathogenesis of AS

SourceGreat article!
HLA-B27

[!INFO] Key points

• It's largely a genetic disease - Patient's children have increased risk of getting it
• Pathogenesis consists of inflammation, bone erosion and syndesmophyte formation.
• Bone erosion and syndesmophyte formation are probably not linked to inflammation
• TNF-blockage suppresses symptoms but doesn't arrest bone changes.
  
  

Clinical features of AS

• Intermittent episodes of sacroiliac joint inflammation
  • Chronic back pain which is reduced by exercise.
• Uveitis and costochondritis suggest back pain of rheumatic origin (i.e AS)
• Peripheral Joint involvement is asymmetrical and involves the large joints.
  • (eg Hip)
  • ankles, hips, knees, shoulders, and the sternoclavicular joints
• Axial joints
  • Formation of syndesmophytes can lead to fusion of vertebrae. (Shobers test detects a stiff spine in early stages)
  • Advanced cases: fusion of the sacroiliac joints, and bamboo spine. (Gadolinum MRI is more sensitive than Xray at detecting early changes).
• Dactylitis - sausage shaped fingers and toes
• Extra-articular manifestations
  • Uveitis - can present as painful eye with photophobia and blurred vision -> emergency!
  • Aortitis

Management of Anky Spondi

• Prevention of syndesmophyte formation -> early diagnosis and initiation of exercise regimen.
• NSAIDS for pain relief to enable exercise during exacerbations.
• MTX -> good for peripheral arthritis but will not work for spinal disease. Only exercise👆
• TNF-α blockers - etanercept and adalimumab provide HUGE symptomatic relief. They reduced morbidity
• Children of affected person have a 30% change of developing anky Spondi.
• Overall prognosis is good with exercise and pain relief, allowing 80% of patients to remain employed.

Aplastic anaemia

#2022GM Q30
Congenital

• fanconi anaemia

• dyskeratosis congenita
• Familiar aplastic anaemia
• Cartillage hair hypoplasia
• Diamond-blackfan anaemia

Acquired

• infection - EBV, hepatitis, parvovirus, mycobacteria
• Ionizing radiation
• Benzene, pesticides
• GVHD
• Pregnancy
• anorexia, severe nutritional deficiencies
• PNH

Hepatosplenomegaly and lymphadenopathy are rare.

[!TIP] Overview
Effective anti epileptic but with unpredictable pharmacology and significant toxic effects.

[!SUMMARY] Phenytoin
Phenytoin is a second line antiepileptic (now used mainly in ED settings) with narrow therapeutic window.
It has multiple side effects.

• Acute toxicity can produce motor symptoms.
• Low protein states, uraemia, and liver dysfunction predispose to toxicity.
• Gum swelling, hypertrichosis and idiosyncratic TEN are important side effects

Mechanism:
Phenytoin binds to and inhibits voltage-dependent sodium channels, which are found on both neuronal and cardiac tissue.

Pharmacokinetics

0 order / zero order kinetics at therapeutic concentrations (saturation kinetics)

• plasma half life increases with dose!
  1st order kinetics at lower concentrations

Narrow therapeutic index.

pharmacodynamics

Enzyme inducer.

Interactions

Valproate displaced phenytoin from bound proteins -> increased risk of toxicity.
Ethanol / Phenobarbital

• -> initially competitively inhibit phenytoin metabolism -> increase phenytoin concentration.
• -> Later, induce phenytoin metabolising enzymes -> decrease phenytoin concentration.

Clinical

Used for GTCs.
Complex partial seizures
Status epilepticus

Phenytoin toxicity

Symptoms : N/V, headache,
motor effects: nystagmus, tremmor, cerebellar ataxia.

10 - 20 - occasional horizontal nystagmus
20 - 30 - nystagmus+
30 - 40 - ataxia, slurred speech, tremmors, NV
40 - 50 - lethargy, confusion and hyperactivity
> 50 mg/L. - Coma and seizures

IV phenytoin can have cardiac effects;
Rare side effect of IV phenytoin : purple glove syndrome: distal oedema of limbs with necrosis.

==Phenytoin worsens primary generalized epilepsies.==
Phenytoin worsens absense seizures and myoclonic seizures.

Management of phenytoin toxicity

Supportive; mortality rate is low.

Phenytoin Vs. Phenobarbitone

Phenytoin is structurally related to the barbiturates.

Types of antiepileptic medications

• Carbamazepine, phenobarbital and phenytoin are "narrow spectrum" -> used mainly for focal onset seizures.
• Clobazam, lamtotrigine, levetiracetam, topiramate, valproate are "broad spectrum" -> used for both focal and generalized seizures.
• Ethosuximide -> used for absence seizures.
  Source

Antiepileptic drugs which may worsen seizures

• Carbamazepine -> can worsen absense, myoclonic and atonic seizures.
• Phenytoin -> can worsen absense, myoclonic seizures.
• Lamotrigine -> can worsen myoclonic seizures
  Chronic use is associate with an increased risk of decreased bone density, Dupuytren contractures, plantar fibromatosis, and frozen shoulder.

Enzyme inducers and inhibitors

[!TIP] left Side - Inhibitors; Right side - INDUCERS,

Protein bound drugs

The free, unbound portion of a drug can be very small. (1%).
The most important protein which binds drugs is albumin.
Albumin binds many acidic drugs - warfarin, NSAIDS, Sulfonamides.
and fewer basic drugs (TCA, chlropromazine).

For most drugs at therapeutic concentration, the carrier proteins very far from saturated.
At these concentrations, bound fraction does not changes with drug concentration.

However, tolbutamide almost completely saturates proteins at therapeutic level. So increasing dose increases the free proportion disproporionately.

Sulfonamides have very high affinity so they occupy about 50% of the binding sites on albumin. This allows sulfonamides to significantly displace other protein bound drugs.

From DerangedPhysiology:

• Clinical significance of drug protein binding:
  • VOD: smaller for drugs with are highly plasma protein bound, larger for drugs which are highly tissue protein-bound
  • Metabolism and clearance: only the free fraction is usually available for dialysis, renal elimination and hepatic metabolism (with some exceptions)
  • Measured drug levels: total drug level may underrepresented clinically relevant concentration of free biologically active drug if there is hypoalbuminaemia
  • Displacement by other drugs, where there is competition for binding sites.

Selected drugs which are highly protein bound
Source

1. Phenytoin [[#Phenytoin toxicity]]
2. Warfarin
3. Levothyroxine
4. Ibuprofen, indomethacin,
5. Tolbutamid - contains a sulfa group
6. Acetazolamide
7. Amiodarone

Sulfonamides / sulphonamides

Initially developed as antibacterials; not used much now for that role (because of resistance) except for

1. sulfamethoxazole (given in combination with trimethoprim as co-trimoxazole, i.e TMP-SMX) -> Pneumocystis jirovecii infection, Stenorophomonas
2. Sulfasalazine (poor GI absorption - used for UC and crohn's)
3. Silver sulfadiazine

Non antibacterial sulfonamides

1. prasugrel
2. acetazolamide

There are antimicrobial and non antimicrobial sulfonamides: There's a large list!
List

Sulfonamide-containing nonantimicrobial agents (Table 1) include agents from therapeutic classifications such as thiazide and loop diuretics, carbonic anhydrase inhibitors, nonsteroidal anti-inflammatory drugs, sulfonylureas, antiretrovirals, and 5HT-3 receptor agonists

In the general population, approximately 3–8% of patients are reported to experience a sulfonamide allergy.
Stevens-Johnson syndrome can occur.

[!INFO] Allergy
Although many types of drugs have the NH2-SO2 sulpha group and are therefore technically 'sulfa-drugs', they don't have some additional group which are responsible for the allergies caused by the antibacterial sulphonamides. Therefore, cross reactivity and allergy risk is low.

The nonantimicrobial sulfonamides do not undergo metabolism to the N4-hydroxylated metabolite associated with SJS and will not bind to IgE at the N1 position and, therefore, are unlikely to cause cross-reactivity, even in patients who have experienced type 1 hypersensitivity or serious non-type-1 hypersensitivity reactions to sulfonamide antimicrobial agents.

Drugs Showing Zero order kinetics

A few known drugs show zero order / 0 order kinetics.
==Most drugs show first order kinetics==.
ChatGPT: (verified)

1. Aspirin - At high doses. Low doses -> first order.
2. Phenytoin
3. Ethanol
4. Salicylates other than aspirin (sodium salicylate)
5. Lithium
6. Procainamide
7. Omeprazole
8. fluoxetine
9. cisplatin

Important implications for saturation kinetics:

• Duration of action is more dependent on the dose.
• Plasma concentration is unpredictable

Illustration of the difference of variation in plasma concentration between zero and first order kinetics:

Phenytoin is the classical poster child for non-linear elimination kinetics, because the enzyme saturation point is reached somewhere in the middle of the therapeutic concentration range - Deranged Physiology

1/3 of patients have chronic hepatitis B infection.
11. Somehow, lungs aren't involved.

[!TIP] Mnemonic

1. GPA (Granulomatosis with polyangitis) - Wegener's ganulomatosis
2. EGPA (**Eosinophilic** granulomatosis with polyangiitis)- Churg Strauss syndrome
3. MPA (Microscopic polyangitis) - no other name. 

[!INFO] Types of ANCA antibodies
It was found that the serum of patients with vasculitis would stain neutrophils in one of two pattersn:

1. Perinuclear - this serum has p-ANCA antibodies
2. Cytoplasmic - this serum has c-ANCA antibodies.
   C-ANCA stains neutrophil proteinsase 3 (PR3 ANCA = cANCA)
   P-ANCA stains neurtrophil myeloperoxidase (MPO ANCA = pANCA)
   
   c in C3PO and 3 is also in C3PO

pANCA - MPA and EGPA
cANCA - GPA
" c " in c-ANCA looks like " G " in GPA.